All-oral regimens containing the HCV protease inhibitor ABT-450, a non-nucleoside polymerase inhibitor, and ribavirin led to sustained response for more than 90% of previously untreated patients -- including those with unfavorable IL28B gene patterns -- but only about half of prior non-responders, researchers reported at the 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013) last week in Atlanta.

Direct-acting antiviral agents that target various steps of the hepatitis C virus (HCV) lifecycle have brought about a new treatment paradigm for chronic hepatitis C, and many patients and clinicians are eagerly awaiting all-oral regimens without interferon.

Eric Lawitz from the University of Texas Health Science Center and colleagues compared various interferon-free combinations of direct-acting drugs being developed by AbbVie (formerly Abbott).

All 12-week regimens included the once-daily HCV NS3/4A protease inhibitor ABT-450, boosted with ritonavir (Norvir) to achieve adequate levels in the body (ABT-450/r). They also included a non-nucleoside HCV NS5B polymerase inhibitor -- either ABT-072 taken once daily or ABT-333 taken twice daily -- and 1000-1200 mg/day weight-based ribavirin.

About 70% of participants overall were men (though this varied from about one-half to 100% in different treatment arms), about 80% were white, and the average age was approximately 53 years. About 80% had more difficult-to-treat HCV subtype 1a. In Cohort 4, about 60% were prior partial responders (still-detectable HCV RNA at the end of previous interferon-based therapy) and the rest null responders (less than a 2-logdecline in HCV RNA). People with HIV and hepatitis B coinfection were excluded.

Enrollment in Cohort 1 was restricted to patients with the favorable IL28B CC gene pattern, which is associated with good interferon response; its role in interferon-free therapy is not yet clear. In Cohort 2 half had the CC pattern, about one-third had the CT (intermediate) pattern and about 10% were TT (least favorable). In Cohort 3 the CC and CT proportions were reversed. In Cohort 4 no one had the CC pattern (typical of non-responders) while about 70% were CT and 30% TT.

For the more challenging treatment-experienced participants in Cohort 4, the SVR24 rate fell to just 47%; looking further out to 48 weeks post-treatment, 6 people experienced viral breakthrough while on therapy and 3 relapsed after finishing treatment.

Breaking out the results by IL28B pattern, among the treatment-naive participants SVR24 rates were 85% for people with the CC pattern and 100% for those with either CT or TT, demonstrating that IL28B has no impact on these interferon-free regimens; for non-responders, SVR24 rates were 50% for those with the CT pattern and 40% for those with TT.

1 person who experienced viral breakthrough had a resistance mutation at NS3 protease position D168 at baseline, and almost everyone else with on-treatment breakthrough or post-treatment relapse showed such mutations at the time of treatment failure; NS5B polymerase mutations were more variable, often involving G554 or S556.

All combinations were generally safe and well tolerated.

The most common side-effects were fatigue, nausea, headache, and dizziness. About 13% had elevated bilirubin, which Lawitz explained was due to a known effect of ABT-450 on a bilirubin transporter protein in the liver.

There were no serious adverse events or deaths, and just 1 person in Cohort 2 stopped treatment early due to side effects.

Efficacy and side effects did not differ significantly between the 150 mg and 250 mg ABT-450 doses.

"We're in a state of a paradigm shift to the era of direct-acting antivirals," Lawitz said at an accompanying CROI press conference. "For those with mild-to-moderate disease, as timelines for approval [of direct-acting drugs] firm up, we're using interferon less and putting more people in the warehouse" to wait for interferon-free treatment.